Lupine is a legume commonly used in human diet as a functional food due to its high nutritional content and important technological properties. However, its consumption can lead to the manifestation of adverse immunological reactions, posing significant health issues in sensitized/allergic patients. This work aims to investigate the effect of food processing combined with simulated gastrointestinal (GI) digestion on the immunoreactivity of lupine γ-conglutin. Model foods of wheat pasta containing 35% of lupine flour (Lupinus albus, L. luteus, and L. angustifolius) were prepared and submitted to a boiling process. The proteins were extracted and their profiles characterized by SDS-PAGE. Simulated GI digestion was performed on thermally treated pasta using the INFOGEST harmonized digestion protocol 2.0. The IgG binding capacity of γ-conglutin was assessed by immunoblotting in non-reducing conditions and indirect ELISA with specific antibodies. Results demonstrate that the boiling treatment affected the immunoreactivity of the three lupine species differently. Simulated GI digestion led to extensive destruction of the protein structure, more significant in the intestinal phase, reducing but not abolishing the IgG affinity to γ-conglutin and its potential presentation to immunocompetent cells. This information can offer valuable insights to the food industry for developing food formulations with reduced allergenic properties.